Publications by authors named "Jie Hua"

89 Publications

From the Immune Profile to the Immunoscore: Signatures for Improving Postsurgical Prognostic Prediction of Pancreatic Neuroendocrine Tumors.

Front Immunol 2021 23;12:654660. Epub 2021 Apr 23.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Objective: Immune infiltration plays an important role in tumor development and progression and shows promising prognostic value in numerous tumors. In this study, we aimed to identify the role of immune infiltration in pancreatic neuroendocrine tumors (Pan-NETs) and to establish an Immunoscore system to improve the prediction of postsurgical recurrence-free survival.

Methods: To derive transcriptional signatures and deconvolute specific immune populations, two GEO datasets containing 158 Pan-NET patients were reanalyzed to summarize the immune infiltration landscape and identify immune-related signatures. Using real-time reverse transcription-polymerase chain reaction, immunofluorescence and immunochemistry methods, candidate signatures were further detected. The least absolute shrinkage and selection operator (LASSO) logistic regression model used statistically significant survival predicators in the training cohort (n=125) to build an Immunoscore system. The prognostic and predictive accuracy was validated in an external independent cohort of 77 patients.

Results: The immune infiltration profile in Pan-NETs showed significant heterogeneity, among which accumulated immune cells, T lymphocytes and macrophages were predominant. Fourteen statistically significant immune-related signatures were further identified in the screening cohort. The Immunoscore system for Pan-NETs (ISpnet) consisting of six immune features (CCL19, IL-16, CD163, IRF4, CD8 and CD8) was constructed to classify patients as high and low risk in the training cohort (cutoff value = 2.14). Low-risk patients demonstrated longer 5-year recurrence-free survival (HR, 0.061; 95% CI, 0.026 to 0.14; p < 0.0001), with fewer recurrences and better prognoses. To predict the individual risk of recurrence, a nomogram incorporating both immune signatures and clinicopathological characteristics was developed.

Conclusion: Our model, ISpnet, captures immune feature-associated prognostic indicators in Pan-NETs and represents the first immune feature-based score for the postsurgical prognostic prediction. The nomogram based on the ISpnet and independent clinical risk factors might facilitate decision-making regarding early recurrence risk monitoring, identify high-risk patients in need of adjuvant therapy, and provide auxiliary guidance for patients with Pan-NETs that may benefit from immunotherapy in clinical trials.
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http://dx.doi.org/10.3389/fimmu.2021.654660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102869PMC
April 2021

Identification of the Roles of a Stemness Index Based on mRNA Expression in the Prognosis and Metabolic Reprograming of Pancreatic Ductal Adenocarcinoma.

Front Oncol 2021 12;11:643465. Epub 2021 Apr 12.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Cancer stem cells (CSCs) are widely thought to contribute to the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC). CSCs share biological features with adult stem cells, such as longevity, self-renewal capacity, differentiation, drug resistance, and the requirement for a niche; these features play a decisive role in cancer progression. A prominent characteristic of PDAC is metabolic reprogramming, which provides sufficient nutrients to support rapid tumor cell growth. However, whether PDAC stemness is correlated with metabolic reprogramming remains unknown.

Method: RNA sequencing data of PDAC, including read counts and fragments per kilobase of transcript per million mapped reads (FPKM), were collected from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA-PAAD) database. Single-sample gene set enrichment analysis (GSEA) was used to calculate the relative activities of metabolic pathways in each PDAC sample. Quantitative real-time PCR was performed to validate the expression levels of genes of interest.

Results: The overall survival (OS) of patients with high mRNA expression-based stemness index (mRNAsi) values was significantly worse than that of their counterparts with low mRNAsi values ( = 0.003). This survival disadvantage was independent of baseline clinical characteristics. Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and GSEA showed that the differentially expressed genes between patients with high and low mRNAsi values were mainly enriched in oncogenic and metabolic pathways. Weighted gene coexpression network analysis (WGCNA) revealed 8 independent gene modules that were significantly associated with mRNAsi and 12 metabolic pathways. Unsupervised clustering based on the key genes in each module identified two PDAC subgroups characterized by different mRNAsi values and metabolic activities. Univariate Cox regression analysis identified 14 genes beneficial to OS from 95 key genes selected from the eight independent gene modules from WGCNA. Among them, MAGEH1, MAP3K3, and PODN were downregulated in both pancreatic tissues and cell lines.

Conclusion: The present study showed that PDAC samples with high mRNAsi values exhibited aberrant activation of multiple metabolic pathways, and the patients from whom these samples were obtained had a poor prognosis. Future studies are expected to investigate the underlying mechanism based on the crosstalk between PDAC stemness and metabolic rewiring.
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http://dx.doi.org/10.3389/fonc.2021.643465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071957PMC
April 2021

Inhibiting BDNF/TrkB.T1 receptor improves resiniferatoxin-induced postherpetic neuralgia through decreasing ASIC3 signaling in dorsal root ganglia.

J Neuroinflammation 2021 Apr 19;18(1):96. Epub 2021 Apr 19.

Department of Anesthesiology and Pain Management, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, China.

Background: Postherpetic neuralgia (PHN) is a devastating complication after varicella-zoster virus infection. Brain-derived neurotrophic factor (BDNF) has been shown to participate in the pathogenesis of PHN. A truncated isoform of the tropomyosin receptor kinase B (TrkB) receptor TrkB.T1, as a high-affinity receptor of BDNF, is upregulated in multiple nervous system injuries, and such upregulation is associated with pain. Acid-sensitive ion channel 3 (ASIC3) is involved in chronic neuropathic pain, but its relation with BDNF/TrkB.T1 in the peripheral nervous system (PNS) during PHN is unclear. This study aimed to investigate whether BDNF/TrkB.T1 contributes to PHN through regulating ASIC3 signaling in dorsal root ganglia (DRGs).

Methods: Resiniferatoxin (RTX) was used to induce rat PHN models. Mechanical allodynia was assessed by measuring the paw withdrawal thresholds (PWTs). Thermal hyperalgesia was determined by detecting the paw withdrawal latencies (PWLs). We evaluated the effects of TrkB.T1-ASIC3 signaling inhibition on the behavior, neuronal excitability, and inflammatory response during RTX-induced PHN. ASIC3 short hairpin RNA (shRNA) transfection was used to investigate the effect of exogenous BDNF on inflammatory response in cultured PC-12 cells.

Results: RTX injection induced mechanical allodynia and upregulated the protein expression of BDNF, TrkB.T1, ASIC3, TRAF6, nNOS, and c-Fos, as well as increased neuronal excitability in DRGs. Inhibition of ASIC3 reversed the abovementioned effects of RTX, except for BDNF and TrkB.T1 protein expression. In addition, inhibition of TrkB.T1 blocked RTX-induced mechanical allodynia, activation of ASIC3 signaling, and hyperexcitability of neurons. RTX-induced BDNF upregulation was found in both neurons and satellite glia cells in DRGs. Furthermore, exogenous BDNF activated ASIC3 signaling, increased NO level, and enhanced IL-6, IL-1β, and TNF-α levels in PC-12 cells, which was blocked by shRNA-ASIC3 transfection.

Conclusion: These findings demonstrate that inhibiting BDNF/TrkB.T1 reduced inflammation, decreased neuronal hyperexcitability, and improved mechanical allodynia through regulating the ASIC3 signaling pathway in DRGs, which may provide a novel therapeutic target for patients with PHN.
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http://dx.doi.org/10.1186/s12974-021-02148-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054387PMC
April 2021

Role of tumor mutation burden-related signatures in the prognosis and immune microenvironment of pancreatic ductal adenocarcinoma.

Cancer Cell Int 2021 Apr 7;21(1):196. Epub 2021 Apr 7.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China.

Background: High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. However, whether high TMB predicts the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC) remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC.

Methods: The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study.

Results: The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBMicrosatellite instability (MSI) was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits.

Conclusion: This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.
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http://dx.doi.org/10.1186/s12935-021-01900-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028808PMC
April 2021

Emerging roles of the solute carrier family in pancreatic cancer.

Clin Transl Med 2021 Mar;11(3):e356

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Pancreatic cancer is a gastrointestinal tumor with a high mortality rate, and advances in surgical procedures have only resulted in limited improvements in the prognosis of patients. Solute carriers (SLCs), which rank second among membrane transport proteins in terms of abundance, regulate cellular functions, including tumor biology. An increasing number of studies focusing on the role of SLCs in tumor biology have indicated their relationship with pancreatic cancer. The mechanism of SLC transporters in tumorigenesis has been explored to identify more effective therapies and improve survival outcomes. These transporters are significant biomarkers for pancreatic cancer, the functions of which include mainly proliferative signaling, cell death, angiogenesis, tumor invasion and metastasis, energy metabolism, chemotherapy sensitivity and other functions in tumor biology. In this review, we summarize the different roles of SLCs and explain their potential applications in pancreatic cancer treatment.
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http://dx.doi.org/10.1002/ctm2.356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989705PMC
March 2021

Deciphering the Prognostic Implications of the Components and Signatures in the Immune Microenvironment of Pancreatic Ductal Adenocarcinoma.

Front Immunol 2021 10;12:648917. Epub 2021 Mar 10.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

The treatment modalities for pancreatic ductal adenocarcinoma (PDAC) are limited and unsatisfactory. Although many novel drugs targeting the tumor microenvironment, such as immune checkpoint inhibitors, have shown promising efficacy for some tumors, few of them significantly prolong the survival of patients with PDAC due to insufficient knowledge on the tumor microenvironment. A single-cell RNA sequencing (scRNA-seq) dataset and seven PDAC cohorts with complete clinical and bulk sequencing data were collected for bioinformatics analysis. The relative proportions of each cell type were estimated using the gene set variation analysis (GSVA) algorithm based on the signatures identified by scRNA-seq or previous literature. A meta-analysis of 883 PDAC patients showed that neutrophils are associated with worse overall survival (OS) for PDAC, while CD8+ T cells, CD4+ T cells, and B cells are related to prolonged OS for PDAC, with marginal statistical significance. Seventeen cell categories were identified by clustering analysis based on single-cell sequencing. Among them, CD8+ T cells and NKT cells were universally exhausted by expressing exhaustion-associated molecular markers. Interestingly, signatures of CD8+ T cells and NKT cells predicted prolonged OS for PDAC only in the presence of "targets" for pyroptosis and ferroptosis induction. Moreover, a specific state of T cells with overexpression of ribosome-related proteins was associated with a good prognosis. In addition, the hematopoietic stem cell (HSC)-like signature predicted prolonged OS in PDAC. Weighted gene co-expression network analysis identified 5 hub genes whose downregulation may mediate the observed survival benefits of the HSC-like signature. Moreover, trajectory analysis revealed that myeloid cells evolutionarily consisted of 7 states, and antigen-presenting molecules and complement-associated genes were lost along the pseudotime flow. Consensus clustering based on the differentially expressed genes between two states harboring the longest pseudotime span identified two PDAC groups with prognostic differences, and more infiltrated immune cells and activated immune signatures may account for the survival benefits. This study systematically investigated the prognostic implications of the components of the PDAC tumor microenvironment by integrating single-cell sequencing and bulk sequencing, and future studies are expected to develop novel targeted agents for PDAC treatment.
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http://dx.doi.org/10.3389/fimmu.2021.648917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987951PMC
March 2021

Hyperdense Pancreatic Ductal Adenocarcinoma: Clinical Characteristics and Proteomic Landscape.

Front Oncol 2021 25;11:640820. Epub 2021 Feb 25.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Purpose: Hypodensity of pancreatic ductal adenocarcinoma (PDAC) during contrast-enhanced computed tomography (CECT) examination is common, but a minority of PDAC patients exhibit hyperdense images. The present study examined the clinical characteristics and protein landscape of PDAC with hyperdensity.

Materials And Methods: A total of 844 pathologically confirmed PDAC patients who underwent CECT before surgery were included. During the parenchymal phase of CECT, patients were assigned to the hyperdense or hypodense group based on CT values. Clinical and CT characteristics for predicting relapse-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox proportional hazards model. The expression of the tumor angiogenesis marker CD31 and stroma-related protein CTHRC1 were analyzed using immunohistochemistry (IHC) assay to evaluate differences between the two groups. Proteomics was performed to compare the possible mechanisms underlying the differential enhancement on CT scans.

Results: Based on CECT, 43 and 801 PDAC patients had hyperdense and hypodense lesions, respectively. All 43 patients presented a hyperdense lesion in the parenchymal phase. The mean CECT values of the hyperdense group were higher than the hypodense group (102.5 ± 17.4 and 53.7 ± 18.7, respectively, 0.001). The hyperdense group had a better prognosis than the hypodense group (median RFS, 19.97 vs. 12.34 months, = 0.0176; median OS, 33.6 vs. 20.3 months, = 0.047). Multivariate analysis showed that age, higher CA19-9 levels (> 300 U/ml), tumor stage, tumor differentiation, tumor CT density, and adjuvant chemotherapy were significant independent prognostic factors for OS. CD31 immunohistochemical staining showed that the hyperdense PDACs had a higher microvessel density than the hypodense group ( 0.001). CTHRC1 expression was higher in the hypodense group ( = 0.019). Sixty-eight differentially expressed proteins were found using the tandem mass tag labeling-based quantification of the proteomes of PDAC tissue samples, and 7 proteins (POFUT1, PKP2, P0DOX4, ITPR1, HBG2, IGLC3, SAA2) were related to angiogenesis.

Conclusion: Patients who presented with a hyperdense mass on CECT had a higher microvessel density and better prognosis. Anti-angiogenic therapy may be suitable for these patients.
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http://dx.doi.org/10.3389/fonc.2021.640820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947874PMC
February 2021

Development and multicenter validation of a nomogram for preoperative prediction of lymph node positivity in pancreatic cancer (NeoPangram).

Hepatobiliary Pancreat Dis Int 2021 Apr 5;20(2):163-172. Epub 2021 Jan 5.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. Electronic address:

Background: Neoadjuvant therapy is associated with nodal downstaging and improved oncological outcomes in patients with lymph node (LN)-positive pancreatic cancer. This study aimed to develop and validate a nomogram to preoperatively predict LN-positive disease.

Methods: A total of 558 patients with resected pancreatic cancer were randomly and equally divided into development and internal validation cohorts. Multivariate logistic regression analysis was used to construct the nomogram. Model performance was evaluated by discrimination, calibration, and clinical usefulness. An independent multicenter cohort consisting of 250 patients was used for external validation.

Results: A four-marker signature was built consisting of carbohydrate antigen 19-9 (CA19-9), CA125, CA50, and CA242. A nomogram was constructed to predict LN metastasis using three predictors identified by multivariate analysis: risk score of the four-marker signature, computed tomography-reported LN status, and clinical tumor stage. The prediction model exhibited good discrimination ability, with C-indexes of 0.806, 0.742 and 0.763 for the development, internal validation, and external validation cohorts, respectively. The model also showed good calibration and clinical usefulness. A cut-off value (0.72) for the probability of LN metastasis was determined to separate low-risk and high-risk patients. Kaplan-Meier survival analysis revealed a good agreement of the survival curves between the nomogram-predicted status and the true LN status.

Conclusions: This nomogram enables the identification of pancreatic cancer patients at high risk for LN positivity who may have more advanced disease and thus could potentially benefit from neoadjuvant therapy.
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http://dx.doi.org/10.1016/j.hbpd.2020.12.020DOI Listing
April 2021

Circular RNA in pancreatic cancer: a novel avenue for the roles of diagnosis and treatment.

Theranostics 2021 1;11(6):2755-2769. Epub 2021 Jan 1.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

Pancreatic cancer (PC), an important cause of cancer-related deaths worldwide, is one of the most malignant cancers characterized by a dismal prognosis. Circular RNAs (circRNAs), a class of endogenous ncRNAs with unique covalently closed loops, have attracted great attention in regard to various diseases, especially cancers. Compelling studies have suggested that circRNAs are aberrantly expressed in different cancer tissues and cell types, including PC. More specifically, circRNAs can modify the proliferation, progression, tumorigenesis and chemosensitivity of PC, and some circRNAs could serve as biomarkers for diagnosis and prognosis. Herein, we summarize what is currently known to be related to the biogenesis, functions and potential roles of human circRNAs in PC and their application prospects for PC clinical treatments.
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http://dx.doi.org/10.7150/thno.56174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806488PMC
January 2021

Prognostic value of circulating tumor DNA in pancreatic cancer: a systematic review and meta-analysis.

Aging (Albany NY) 2020 12 9;13(2):2031-2048. Epub 2020 Dec 9.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

Increasing evidence has revealed the potential correlation between circulating tumor DNA (ctDNA) and the prognosis of pancreatic cancer, but inconsistent findings have been reported. Therefore, a meta-analysis was performed to evaluate the prognostic value of ctDNA in pancreatic cancer. The Embase, MEDLINE, and Web of Science databases were searched for relevant articles published until April 2020. Articles reporting the correlation between ctDNA and the prognosis of pancreatic cancer were identified through database searches. The pooled hazard ratios (HRs) for prognostic data were calculated and analyzed using Stata software. A total of 2326 patients pooled from 25 eligible studies were included in the meta-analysis to evaluate the prognostic value of ctDNA in pancreatic cancer. Patients with mutations detected or high concentrations of ctDNA had a significantly poorer overall survival (OS) (univariate: HR = 2.54; 95% CI, 2.05-3.14; multivariate: HR = 2.07; 95% CI, 1.69-2.54) and progression-free survival (PFS) (univariate: HR = 2.18; 95% CI, 1.41-3.37; multivariate: HR = 2.20; 95% CI, 1.38-3.52). In conclusion, the present meta-analysis indicates that mutations detected or high concentrations of ctDNA are significant predictors of OS and PFS in patients with pancreatic cancer.
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http://dx.doi.org/10.18632/aging.202199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880399PMC
December 2020

Platelet-rich plasma improves chronic inflammatory pain by inhibiting PKM2-mediated aerobic glycolysis in astrocytes.

Ann Transl Med 2020 Nov;8(21):1456

Department of Anesthesiology and Pain Management, the First Affiliated Hospital of Soochow University, Suzhou, China.

Background: Astrocytes are highly glycolytic cells that play a crucial role in chronic pain. Recently it has been found that inflammation and metabolism are related to the inflammatory stimuli closely that cause cellular metabolic changes. Pyruvate kinase M2 (PKM2) is a critical metabolic kinase in aerobic glycolysis or the Warburg effect. Besides, it also plays a crucial role in cell proliferation and signal transduction, but its role in astrocytes is still unclear.

Methods: The chronic inflammatory pain model was set up by intraplantar injection of complete Freund's adjuvant (CFA) in Sprague Dawley (SD) rats as well as the cell model was constructed by lipopolysaccharide-treated primary astrocytes. Von Frey filament stimulation was used to continuously observe the changes of pain behavior in rats after modeling. Then, immunofluorescence staining and Western blot tests were used to observe the expression levels of glial fibrillary acidic protein (GFAP), pyruvate kinase (PKM2), signal transducers and activators of transcription 3 (STAT3) and high mobility group box-1 protein (HMGB1). After that, specific kits measured lactate contents. Finally, we observed the platelet-rich plasma's (PRP) effect on mechanical hyperalgesia in rats with inflammatory pain induced by CFA and its effect on related signal molecules.

Results: We found that in the CFA-induced inflammatory pain model, astrocytes were significantly activated, GFAP was increased, PKM2 was significantly up-regulated, and the glycolytic product lactate was increased. Also, intrathecal injection of PRP increased the pain threshold, inhibited the activation of astrocytes, and decreased the expression of PKM2 and aerobic glycolysis; in LPS-activated primary astrocytes as an model, we found PKM2 translocation activationSTAT3 signaling resulted in sustained activation of astrocyte marker GFAP, and the expression level and localization of p-STAT3 were correlated with PKM2. PRP could inhibit the activation of astrocytes, reduce the expression of PKM2 and the expression levels of glycolysis and GFAP, GLUT1, and p-STAT3 in astrocytes.

Conclusions: Our findings suggest PKM2 not only plays a glycolytic role in astrocytes, but also plays a crucial role in astrocyte-activated signaling pathways, and PRP attenuates CFA induced inflammatory pain by inhibiting aerobic glycolysis in astrocytes, providing a new therapeutic target for the treatment of inflammatory pain.
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http://dx.doi.org/10.21037/atm-20-6502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723564PMC
November 2020

The role of ferroptosis regulators in the prognosis, immune activity and gemcitabine resistance of pancreatic cancer.

Ann Transl Med 2020 Nov;8(21):1347

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Ferroptosis is a novel form of regulated cell death that can inhibit the progression of chemotherapy-resistant tumors. However, the types of cancer most susceptible to ferroptosis induction and the role of ferroptosis regulators in cancers, especially pancreatic cancer, remain unclear.

Methods: RNA sequencing data of 31 cancers were collected from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx). A nomogram integrating patients' clinical information and risk scores based on the expression levels of ferroptosis regulators was depicted. Correlations among the activity levels of 29 immunity-associated gene sets, immune scores, infiltrating immune cells and key ferroptosis regulators were assessed.

Results: We performed a pan-cancer analysis and identified 14 distinct cancers that may show a robust response to ferroptosis inducers. Interestingly, the Xc-complex, which is the major target of ferroptosis induction, was upregulated in gemcitabine-resistant pancreatic cancer cells (P<0.05). Furthermore, we focused on the role of ferroptosis regulators in mediating the survival of patients with pancreatic cancer and constructed a prognostic model with good accuracy (AUC =0.713). We also correlated elevated sensitivity to ferroptosis with higher scores for CD8+ T cells (P<0.001), the type two interferon response (P<0.001) and immune checkpoints (P<0.05).

Conclusions: We hypothesized that the ferroptosis pathway plays an important role in the prognosis of pancreatic cancer. Immuno- and chemotherapy combined with a ferroptosis inducer is a feasible therapeutic approach for pancreatic cancer.
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http://dx.doi.org/10.21037/atm-20-2554aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723621PMC
November 2020

The value of a metabolic reprogramming-related gene signature for pancreatic adenocarcinoma prognosis prediction.

Aging (Albany NY) 2020 11 20;12(23):24228-24241. Epub 2020 Nov 20.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. Extensive enhancement of glycolysis and reprogramming of lipid metabolism are both associated with the development and progression of PDAC. Previous studies have suggested that various gene signatures could convey prognostic information about PDAC. However, the use of these signatures has some limitations, perhaps because of a lack of knowledge regarding the genetic and energy supply backgrounds of PDAC. Therefore, we conducted multi-mRNA analysis based on metabolic reprogramming to identify novel signatures for accurate prognosis prediction in PDAC patients. In this study, a three-gene signature comprising MET, ENO3 and CD36 was established to predict the overall survival of PDAC patients. The three-gene signature could divide patients into high- and low-risk groups by disparities in overall survival verified by log-rank test in two independent validation cohorts and could differentiate tumors from normal tissues with excellent accuracy in four Gene Expression Omnibus (GEO) cohorts. We also found a positive correlation between the risk score of the gene signature and inherited germline mutations in PDAC predisposition genes. A glycolysis and lipid metabolism-based gene nomogram and corresponding calibration curves showed significant performance for survival prediction in the TCGA-PDAC dataset. The high-risk designation was closely connected with oncological signatures and multiple aggressiveness-related pathways, as determined by gene set enrichment analysis (GSEA). In summary, our study developed a three-gene signature and established a prognostic nomogram that objectively predicted overall survival in PDAC. The findings could provide a reference for the prediction of overall survival and could aid in individualized management for PDAC patients.
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http://dx.doi.org/10.18632/aging.104134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762467PMC
November 2020

The promising role of noncoding RNAs in cancer-associated fibroblasts: an overview of current status and future perspectives.

J Hematol Oncol 2020 11 19;13(1):154. Epub 2020 Nov 19.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China.

As the most important component of the stromal cell population in the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) are crucial players in tumor initiation and progression. The interaction between CAFs and tumor cells, as well as the resulting effect, is much greater than initially expected. Numerous studies have shown that noncoding RNAs (ncRNAs) play an irreplaceable role in this interplay, and related evidence continues to emerge and advance. Under the action of ncRNAs, normal fibroblasts are directly or indirectly activated into CAFs, and their metabolic characteristics are changed; thus, CAFs can more effectively promote tumor progression. Moreover, via ncRNAs, activated CAFs can affect the gene expression and secretory characteristics of cells, alter the TME and enhance malignant biological processes in tumor cells to contribute to tumor promotion. Previously, ncRNA dysregulation was considered the main mechanism by which ncRNAs participate in the crosstalk between CAFs and tumor cells. Recently, however, exosomes containing ncRNAs have been identified as another vital mode of interaction between these two types of cells, with a more direct and clear function. Gaining an in-depth understanding of ncRNAs in CAFs and the complex regulatory network connecting CAFs with tumor cells might help us to establish more effective and safer approaches for cancer therapies targeting ncRNAs and CAFs and offer new hope for cancer patients.
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http://dx.doi.org/10.1186/s13045-020-00988-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678062PMC
November 2020

Acetyl-11-keto-β-boswellic acid inhibits proliferation and induces apoptosis of gastric cancer cells through the phosphatase and tensin homolog /Akt/ cyclooxygenase-2 signaling pathway.

World J Gastroenterol 2020 Oct;26(38):5822-5835

Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China.

Background: Gastric cancer is one of the most common malignant tumors of the digestive system worldwide, posing a serious danger to human health. Cyclooxygenase (COX)-2 plays an important role in the carcinogenesis and progression of gastric cancer. Acetyl-11-keto-β-boswellic acid (AKBA) is a promising drug for cancer therapy, but its effects and mechanism of action on human gastric cancer remain unclear.

Aim: To evaluate whether the phosphatase and tensin homolog (PTEN)/Akt/COX-2 signaling pathway is involved in the anti-tumor effect of AKBA in gastric cancer.

Methods: Human poorly differentiated BGC823 and moderately differentiated SGC7901 gastric cancer cells were routinely cultured in Roswell Park Memorial Institute 1640 medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. Gastric cancer cell proliferation was determined by methyl thiazolyl tetrazolium colorimetric assay. Apoptosis was measured by flow cytometry. Cell migration was assessed using the wound-healing assay. Expression of Bcl-2, Bax, proliferating cell nuclear antigen, PTEN, p-Akt, and COX-2 were detected by Western blot analysis. A xenograft nude mouse model of human gastric cancer was established to evaluate the anti-cancer effect of AKBA .

Results: AKBA significantly inhibited the proliferation of gastric cancer cells in a dose- and time-dependent manner, inhibited migration in a time-dependent manner, and induced apoptosis in a dose-dependent manner ; it also inhibited tumor growth . AKBA up-regulated the expression of PTEN and Bax, and down-regulated the expression of proliferating cell nuclear antigen, Bcl-2, p-Akt, and COX-2 in a dose-dependent manner. The PTEN inhibitor bpv (Hopic) reversed the high expression of PTEN and low expression of p-Akt and COX-2 that were induced by AKBA. The Akt inhibitor MK2206 combined with AKBA down- regulated the expression of p-Akt and COX-2, and the combined effect was better than that of AKBA alone.

Conclusion: AKBA inhibits the proliferation and migration and promotes the apoptosis of gastric cancer cells through the PTEN/Akt/COX-2 signaling pathway.
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http://dx.doi.org/10.3748/wjg.v26.i38.5822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579763PMC
October 2020

ELNet:Automatic classification and segmentation for esophageal lesions using convolutional neural network.

Med Image Anal 2021 01 7;67:101838. Epub 2020 Oct 7.

Department of Medical Imaging, Western University, London, Canada.

Automatic and accurate esophageal lesion classification and segmentation is of great significance to clinically estimate the lesion statuses of the esophageal diseases and make suitable diagnostic schemes. Due to individual variations and visual similarities of lesions in shapes, colors, and textures, current clinical methods remain subject to potential high-risk and time-consumption issues. In this paper, we propose an Esophageal Lesion Network (ELNet) for automatic esophageal lesion classification and segmentation using deep convolutional neural networks (DCNNs). The underlying method automatically integrates dual-view contextual lesion information to extract global features and local features for esophageal lesion classification and lesion-specific segmentation network is proposed for automatic esophageal lesion annotation at pixel level. For the established clinical large-scale database of 1051 white-light endoscopic images, ten-fold cross-validation is used in method validation. Experiment results show that the proposed framework achieves classification with sensitivity of 0.9034, specificity of 0.9718, and accuracy of 0.9628, and the segmentation with sensitivity of 0.8018, specificity of 0.9655, and accuracy of 0.9462. All of these indicate that our method enables an efficient, accurate, and reliable esophageal lesion diagnosis in clinics.
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http://dx.doi.org/10.1016/j.media.2020.101838DOI Listing
January 2021

The role of m6A-related genes in the prognosis and immune microenvironment of pancreatic adenocarcinoma.

PeerJ 2020 28;8:e9602. Epub 2020 Sep 28.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Pancreatic adenocarcinoma (PAAD) is among the most lethal diseases and has a dismal prognosis; however, efficient treatment is currently limited. Several studies have observed epigenetic variation during tumorigenesis, suggesting the potential role of RNA methylation, especially N6-methyladenosine (m6A) modification, as a novel epigenetic modification mediating PAAD prognosis.

Methods: The expression levels of m6A-related genes were downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA) and Genotype-Tissue Expression (GTEx) projects, and the findings were validated in four Expression Omnibus (GEO) datasets. A predictive model was constructed using a lasso regression and evaluated by a survival analysis and receiver operating characteristic curve. Consensus clustering identified two distinct subgroups with different immune activity signatures based on the expression pattern of m6A-related genes. The relationship between the mutation state of m6A-related genes and infiltration of immune cells was established and visualized using Tumor Immune Estimation Resource (https://cistrome.shinyapps.io/timer/).

Results: Fourteen of twenty-one m6A-related genes were differentially expressed between PAAD and normal tissues in TCGA-GTEx cohort. Among these genes, and were further validated in four GEO datasets. Moreover, an m6A-based model exhibited moderate accuracy in predicting overall survival in PAAD samples. Additionally, potential m6A modification targets were screened by selecting genes from a set of 23,391 genes that not only harbored the most m6A-modified sites but also showed a robust correlation with PAAD survival. Moreover, we correlated the expression level of m6A-related genes with the immune microenvironment of pancreatic cancer for the first time. Specifically, both arm-level gain and deletion of decreased the infiltration of CD8+T cells ( < 0.05 and  < 0.01, respectively).

Conclusion: Collectively, our findings suggest a novel anticancer strategy for restoring balanced RNA methylation in tumor cells and guide clinical physicians in developing a new practical approach for considering the impact of related genes on prognosis.
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http://dx.doi.org/10.7717/peerj.9602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528816PMC
September 2020

Ferroptosis, necroptosis, and pyroptosis in anticancer immunity.

J Hematol Oncol 2020 08 10;13(1):110. Epub 2020 Aug 10.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, China.

In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved considerable success in the clinic. However, ICIs are significantly limited by the fact that only one third of patients with most types of cancer respond to these agents. The induction of cell death mechanisms other than apoptosis has gradually emerged as a new cancer treatment strategy because most tumors harbor innate resistance to apoptosis. However, to date, the possibility of combining these two modalities has not been discussed systematically. Recently, a few studies revealed crosstalk between distinct cell death mechanisms and antitumor immunity. The induction of pyroptosis, ferroptosis, and necroptosis combined with ICIs showed synergistically enhanced antitumor activity, even in ICI-resistant tumors. Immunotherapy-activated CD8+ T cells are traditionally believed to induce tumor cell death via the following two main pathways: (i) perforin-granzyme and (ii) Fas-FasL. However, recent studies identified a new mechanism by which CD8+ T cells suppress tumor growth by inducing ferroptosis and pyroptosis, which provoked a review of the relationship between tumor cell death mechanisms and immune system activation. Hence, in this review, we summarize knowledge of the reciprocal interaction between antitumor immunity and distinct cell death mechanisms, particularly necroptosis, ferroptosis, and pyroptosis, which are the three potentially novel mechanisms of immunogenic cell death. Because most evidence is derived from studies using animal and cell models, we also reviewed related bioinformatics data available for human tissues in public databases, which partially confirmed the presence of interactions between tumor cell death and the activation of antitumor immunity.
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http://dx.doi.org/10.1186/s13045-020-00946-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418434PMC
August 2020

Comment on "Prognosis-Based Definition of Resectability in Pancreatic Cancer: A Road Map to New Guidelines".

Ann Surg 2020 Jul 24. Epub 2020 Jul 24.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China Pancreatic Cancer Multidisciplinary Center, Fudan University Shanghai Cancer Center, Shanghai, China Shanghai Pancreatic Cancer Institute, Shanghai, China Pancreatic Cancer Institute, Fudan University, Shanghai, China.

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http://dx.doi.org/10.1097/SLA.0000000000004291DOI Listing
July 2020

Neoadjuvant Treatment for Pancreatic Cancer: Still a Controversial Issue?

J Clin Oncol 2020 09 23;38(25):2943-2944. Epub 2020 Jun 23.

Si Shi, MD; Jie Hua, MD and Xianjun Yu, MD, PhD, Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

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http://dx.doi.org/10.1200/JCO.20.00631DOI Listing
September 2020

A Visual Approach for the SARS (Severe Acute Respiratory Syndrome) Outbreak Data Analysis.

Int J Environ Res Public Health 2020 06 3;17(11). Epub 2020 Jun 3.

Faculty of Information Engineering, Shaoyang University, Shaoyang 422000, China.

Virus outbreaks are threats to humanity, and coronaviruses are the latest of many epidemics in the last few decades in the world. SARS-CoV (Severe Acute Respiratory Syndrome Associated Coronavirus) is a member of the coronavirus family, so its study is useful for relevant virus data research. In this work, we conduct a proposed approach that is non-medical/clinical, generate graphs from five features of the SARS outbreak data in five countries and regions, and offer insights from a visual analysis perspective. The results show that prevention measures such as quarantine are the most common control policies used, and areas with strict measures did have fewer peak period days; for instance, Hong Kong handled the outbreak better than other areas. Data conflict issues found with this approach are discussed as well. Visual analysis is also proved to be a useful technique to present the SARS outbreak data at this stage; furthermore, we are proceeding to apply a similar methodology with more features to future COVID-19 research from a visual analysis perfective.
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http://dx.doi.org/10.3390/ijerph17113973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312089PMC
June 2020

Automatic classification of esophageal lesions in endoscopic images using a convolutional neural network.

Ann Transl Med 2020 Apr;8(7):486

Laboratory of Image Science and Technology, School of Computer Science and Engineering, Southeast University, Nanjing 211102, China.

Background: Using deep learning techniques in image analysis is a dynamically emerging field. This study aims to use a convolutional neural network (CNN), a deep learning approach, to automatically classify esophageal cancer (EC) and distinguish it from premalignant lesions.

Methods: A total of 1,272 white-light images were adopted from 748 subjects, including normal cases, premalignant lesions, and cancerous lesions; 1,017 images were used to train the CNN, and another 255 images were examined to evaluate the CNN architecture. Our proposed CNN structure consists of two subnetworks (O-stream and P-stream). The original images were used as the inputs of the O-stream to extract the color and global features, and the pre-processed esophageal images were used as the inputs of the P-stream to extract the texture and detail features.

Results: The CNN system we developed achieved an accuracy of 85.83%, a sensitivity of 94.23%, and a specificity of 94.67% after the fusion of the 2 streams was accomplished. The classification accuracy of normal esophagus, premalignant lesion, and EC were 94.23%, 82.5%, and 77.14%, respectively, which shows a better performance than the Local Binary Patterns (LBP) + Support Vector Machine (SVM) and Histogram of Gradient (HOG) + SVM methods. A total of 8 of the 35 (22.85%) EC lesions were categorized as premalignant lesions because of their slightly reddish and flat lesions.

Conclusions: The CNN system, with 2 streams, demonstrated high sensitivity and specificity with the endoscopic images. It obtained better detection performance than the currently used methods based on the same datasets and has great application prospects in assisting endoscopists to distinguish esophageal lesion subclasses.
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http://dx.doi.org/10.21037/atm.2020.03.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210177PMC
April 2020

Myrrh induces the apoptosis and inhibits the proliferation and migration of gastric cancer cells through down-regulating cyclooxygenase-2 expression.

Biosci Rep 2020 05;40(5)

Department of Geriatrics, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, China.

Objective: The present study is designed to evaluate the anti-tumor effects of myrrh on human gastric cancer both in vitro and in vivo.

Methods: The gastric cancer cell proliferation was determined by MTT assay. Apoptosis was measured by flow cytometry and Hoechst 33342 staining. Wound healing was performed to evaluate the effects of myrrh on the migration. COX-2, PCNA, Bcl-2, and Bax expressions were detected by Western blot analysis. A xenograft nude mice model of human gastric cancer was established to evaluate the anti-cancer effect of myrrh in vivo.

Results: Myrrh significantly inhibited cellular proliferation, migration, and induced apoptosis in vitro as well as inhibited tumor growth in vivo. In addition, myrrh inhibited the expression of PCNA, COX-2, and Bcl-2 as well as increased Bax expression in gastric cancer cells.

Conclusion: Myrrh may inhibit the proliferation and migration of gastric cancer cells, as well as induced their apoptosis by down-regulating the expression of COX-2.
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http://dx.doi.org/10.1042/BSR20192372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240199PMC
May 2020

A miR-146a-5p/TRAF6/NF-kB p65 axis regulates pancreatic cancer chemoresistance: functional validation and clinical significance.

Theranostics 2020 4;10(9):3967-3979. Epub 2020 Mar 4.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

: Dysregulated microRNA (miRNA) expression in cancer can act as a key factor that modifies biological processes, including chemoresistance. Our study aimed to identify the miRNAs associated with gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC) and to explore the potential mechanisms. : The miRNA microarray was used to identify miRNAs associated with GEM resistance. Quantitative real-time PCR was used to examine miR-146a-5p expression in paired PDAC and adjacent normal tissues. Bioinformatics analysis, luciferase reporter assays, and chromatin immunoprecipitation assays were used to confirm tumor necrosis factor receptor-associated factor 6 (TRAF6) as a direct target of miR-146a-5p and to explore the potential transcription factor binding and regulation by miR-146a-5p. and experiments were performed to investigate the mechanisms. : MiR-146a-5p expression was significantly decreased in PDAC tissues compared with adjacent normal tissues, and miR-146a-5p expression correlated with prognosis in PDAC patients. Functional studies indicated that miR-146a-5p suppressed PDAC cell proliferation and sensitized PDAC cells to GEM chemotherapy by targeting the 3'-untranslated region (3'-UTR) of TRAF6. MiR-146a-5p was also observed to downregulate the TRAF6/NF-κB p65/P-gp axis, which regulates PDAC cell growth and chemoresistance. : Taken together, the results indicate that the miR-146a-5p/TRAF6/NF-κB p65 axis drives pancreatic chemoresistance by regulating P-gp, suggesting that miR-146a-5p may be utilized as a new therapeutic target and prognostic marker in PDAC patients.
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http://dx.doi.org/10.7150/thno.40566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086345PMC
March 2020

Expression Patterns and Prognostic Value of DNA Damage Repair Proteins in Resected Pancreatic Neuroendocrine Neoplasms.

Ann Surg 2020 Mar 20. Epub 2020 Mar 20.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Objective: This study aimed to examine the expression profiles and prognostic value of multiple DDR proteins in resected PanNENs.

Background: DDR proteins play important roles in various cancers, including pancreatic ductal adenocarcinoma. However, the expression patterns and prognostic value of DDR proteins in PanNENs remain unclear.

Methods: This retrospective analysis included PanNEN patients who underwent resection at the Fudan University Shanghai Cancer Center from 2012 to 2018. Immunohistochemical staining was performed for 12 DDR proteins in tissue microarrays. The associations of DDR protein expression and clinicopathological features with recurrence-free survival (RFS) were examined via a Cox regression model and random survival forest. A recurrence signature was constructed using recursive partitioning analysis.

Results: In total, 131 PanNEN patients were included, with 32 (24.4%) cases of recurrence. Among the 12 DDR proteins, low checkpoint kinase 2 (CHK2) expression (P = 0.020) and loss of ataxia-telangiectasia-mutated (ATM) (P = 0.0007) significantly correlated with recurrence. Multivariable Cox regression analysis identified tumor size ≥3 cm, lymph node (LN) metastasis, high tumor grade, low CHK2 expression, and ATM loss as independent risk factors for recurrence. A recurrence signature was established based on the importance of recurrence-specific risk factors; patients with the LNnegTumorSize<3cm signature had a 5-year RFS rate of 96.8%, whereas patients with the LNposCHK2low signature had the worst 5-year RFS rate (0%). Discrimination (concordance index: 0.770) and calibration plots indicated that the recurrence signature had a good ability to identify patients at risk for recurrence.

Conclusions: By analyzing large-scale tissue microarrays of PanNENs, we evaluated 12 DDR protein expression profiles. We developed a recurrence signature that can identify distinct subpopulations according to RFS, which may help refine individual follow-up.
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http://dx.doi.org/10.1097/SLA.0000000000003884DOI Listing
March 2020

Differentiation of solid-pseudopapillary tumors of the pancreas from pancreatic neuroendocrine tumors by using endoscopic ultrasound.

Clin Res Hepatol Gastroenterol 2020 11 3;44(6):947-953. Epub 2020 Mar 3.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China. Electronic address:

Background And Aim: To differentiate solid-pseudopapillary tumors (SPTs) of the pancreas from pancreatic neuroendocrine tumors (pNETs) by endoscopic ultrasound.

Methods: We retrospectively reviewed all patients with SPTs and pNETs who underwent endoscopic ultrasound (EUS) from May 2012 to August 2018 at the Fudan University Shanghai Cancer Center. We included patients confirmed pathologically with a surgical biopsy or with endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). The demographic data of the patients, characteristics of the lesions and overall survival data of patients with these two diseases were further compared.

Results: A total of 147 pNET patients and 21 SPT patients were included in our study. The mean ages of the patients in the SPT and pNET groups were 35.95years and 54.30years, respectively. There were more females in the SPT group than in the pNET group (71.43% vs. 40.82%). The patients in the pNET group had significantly more lymphatic metastases and visceral organ metastases than the patients in the SPT group. A larger proportion of pNET lesions than SPT lesions had homogeneous echo patterns and were hypervascular. Cystic components and calcification components were more often observed in the SPT lesions than in the pNET lesions. In the multivariate logistic regression analysis, the hypervascularization (OR: 6.528, 95% CI: 1.562-27.285, P=0.010) and cystic component (OR: 0.106, 95% CI: 0.019-0.597, P=0.011) variables resulted in the best discrimination of patients with SPTs from patients with pNETs. Survival among patients with SPTs was higher than that among patients with pNETs at all points in the follow-up period.

Conclusions: SPTs tended to occur in younger people and were more common in women. Pancreatic neuroendocrine tumors tended to form metastases more often than SPTs. The blood supply and cystic components of the lesions may have novel potential diagnostic utility for differentiating SPTs from pNETs.
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http://dx.doi.org/10.1016/j.clinre.2020.02.002DOI Listing
November 2020

PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications.

Mol Cancer 2020 03 2;19(1):49. Epub 2020 Mar 2.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

Pancreatic cancer is a highly lethal disease with a poor prognosis, and existing therapies offer only limited effectiveness. Mutation gene sequencing has shown several gene associations that may account for its carcinogenesis, revealing a promising research direction. Poly (ADP-ribose) polymerase (PARP) inhibitors target tumor cells with a homologous recombination repair (HRR) deficiency based on the concept of synthetic lethality. The most prominent target gene is BRCA, in which mutations were first identified in breast cancer and ovarian cancer. PARP inhibitors can trap the PARP-1 protein at a single-stranded break/DNA lesion and disrupt its catalytic cycle, ultimately leading to replication fork progression and consequent double-strand breaks. For tumor cells with BRCA mutations, HRR loss would result in cell death. Pancreatic cancer has also been reported to have a strong relationship with BRCA gene mutations, which indicates that pancreatic cancer patients may benefit from PARP inhibitors. Several clinical trials are being conducted and have begun to yield results. For example, the POLO (Pancreatic Cancer Olaparib Ongoing) trial has demonstrated that the median progression-free survival was observably longer in the olaparib group than in the placebo group. However, PARP inhibitor resistance has partially precluded their use in clinical applications, and the major mechanism underlying this resistance is the restoration of HRR. Therefore, determining how to use PARP inhibitors in more clinical applications and how to avoid adverse effects, as well as prognosis and treatment response biomarkers, require additional research. This review elaborates on future prospects for the application of PARP inhibitors in pancreatic cancer.
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http://dx.doi.org/10.1186/s12943-020-01167-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053129PMC
March 2020

Prognostic Value of Pancreatic Fistula in Resected Patients With Pancreatic Cancer With Neoadjuvant Therapy.

JAMA Surg 2020 03;155(3):267-268

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

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http://dx.doi.org/10.1001/jamasurg.2019.5089DOI Listing
March 2020

Role of Damage DNA-Binding Protein 1 in Pancreatic Cancer Progression and Chemoresistance.

Cancers (Basel) 2019 Dec 12;11(12). Epub 2019 Dec 12.

Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai 200032, China.

Damaged DNA-binding protein 1 (DDB1) recruits nucleotide excision pathway proteins to form the UV-damaged DNA-binding protein complex and is required for DNA repair. DDB1 was reported to participate in apoptosis and chemoresistance regulation in several cancers. However, little is known about the function of DDB1 in pancreatic adenocarcinoma (PDAC). In this study, we reported that DDB1 functions as a tumor-promoting factor in PDAC by regulating cancer cell proliferation, epithelial-mesenchymal transition (EMT) and chemoresistance. Compared to normal pancreatic tissues, PDAC tissues had high expression levels of DDB1, and this high expression was positively correlated with poor prognosis. Furthermore, reductions in cell proliferation and EMT were observed in DDB1-deficient PDAC cell lines. Intriguingly, we also found that abrogation of DDB1 expression increased PDAC cell sensitivity to gemcitabine (GEM). Mechanistically, DDB1 knockdown was associated with an increase in deoxycytidine kinase expression in vivo and in vitro. In summary, our work demonstrated that DDB1 promotes PDAC progression and chemoresistance and may serve as a potential predictive marker and therapeutic target for PDAC treatment.
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http://dx.doi.org/10.3390/cancers11121998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966444PMC
December 2019

The reciprocal regulation between host tissue and immune cells in pancreatic ductal adenocarcinoma: new insights and therapeutic implications.

Mol Cancer 2019 12 13;18(1):184. Epub 2019 Dec 13.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and is one of the most difficult-to-treat cancers. Surgical resection and adjuvant therapy have limited effects on the overall survival of PDAC patients. PDAC exhibits an immunosuppressive microenvironment, the immune response predicts survival, and activation of immune system has the potential to produce an efficacious PDAC therapy. However, chimeric antigen receptor T (CAR-T) cell immunotherapy and immune checkpoint blockade (ICB), which have produced unprecedented clinical benefits in a variety of different cancers, produce promising results in only some highly selected patients with PDAC. This lack of efficacy may be because existing immunotherapies mainly target the interactions between cancer cells and immune cells. However, PDAC is characterized by an abundant tumor stroma that includes a heterogeneous mixture of immune cells, fibroblasts, endothelial cells, neurons and some molecular events. Immune cells engage in extensive and dynamic crosstalk with stromal components in the tumor tissue in addition to tumor cells, which subsequently impacts tumor suppression or promotion to a large extent. Therefore, exploration of the interactions between the stroma and immune cells may offer new therapeutic opportunities for PDAC. In this review, we discuss how infiltrating immune cells influence PDAC development and explore the contributions of complex components to the immune landscape of tumor tissue. The roles of stromal constituents in immune modulation are emphasized. We also predict potential therapeutic strategies to target signals in the immune network in the abundant stromal microenvironment of PDAC.
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http://dx.doi.org/10.1186/s12943-019-1117-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909567PMC
December 2019